Deane R, Sagare A, Hamm K, Parisi M, Lane S, Finn MB, Holtzman DM, Zlokovic BV.
apoE isoform-specific disruption of amyloid beta peptide clearance from mouse brain.
J Clin Invest. 2008 Dec;118(12):4002-13.
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This paper addresses a fundamental question regarding the increased risk of AD in ApoE4 carriers. The results demonstrate that E4 is less effective at clearing the Aβ peptide from brain due to preference for a alternate receptor. Assuming this translates to human brain, the data argue that ApoE4 increases risk due to delayed Aβ clearance, presumably leading to higher brain levels of Aβ peptide (although export is not the sole means of Aβ clearance in brain, it is a significant factor). Overall, this adds further support for Aβ as an instigating factor in Alzheimer dementia, as ApoE4 is a factor in roughly half the cases.
APOE is the strongest genetic risk factor for late onset Alzheimer’s disease. In the brain, among its many functions, ApoE delivers lipid particles to cells, promotes lipid efflux from cells, provides neuroprotective signals to neurons, and inhibits glial inflammation. In this work, Deane et al. examine another function of ApoE: the transport of material out of the brain. They have injected radioactively labeled proteins into the brain, and followed their transport to the blood.
Deane et al. used several compelling techniques to disrupt and define specific pathways of transport, confirming their earlier findings that the Aβ peptide uses the LRP1 molecule to cross from the CNS to the periphery. They report that ApoE also uses LRP1 and the related protein VLDLR for transcytosis, and that ApoE4 slows the transport of Aβ. They also very interestingly find that this transport is dependent on the isoform of ApoE: ApoE2 and ApoE3 use both LRP1 and VLDLR, but ApoE4 only uses VLDLR. Partially because VLDLR has a much slower turnover from the cell surface than LRP1, ApoE4 leaves the brain more slowly and is associated with the least level of efflux of Aβ.
These data are particularly interesting with regard to the recent published findings of Vitek et al., 2008 and of Riddell et al., 2008, who found in APOE targeted replacement mice that brain ApoE levels were lowest in mice expressing ApoE4, compared to ApoE2 or ApoE3. So despite the fact that ApoE4 is the least efficient at leaving the brain, it is nonetheless present in the brain at the lowest levels. Thus, ApoE4 is likely disrupted in both its production and its trafficking. If the findings in the microvasculature translate to other cell types, ApoE interactions with receptors on other cells would also be altered. Brain LRP1 is present primarily in neurons, whereas VLDLR is strongly expressed in microglia. Thus, ApoE2 and ApoE3 might interact more with neurons, and ApoE4 more with microglia.
These findings need to be expanded to endogenously produced ApoE isoforms, as in the APOE targeted replacement mice. Even so, they do indicate that ApoE isoforms differ in their interactions with ApoE receptors, which greatly affect the brain functions of ApoE. Given the strength of the risk factor APOE, it would not be surprising if ApoE isoforms differed in several functions that each contributed to the disease process.
Vitek MP, Brown CM, Colton CA.
APOE genotype-specific differences in the innate immune response.
Neurobiol Aging. 2009 Sep;30(9):1350-60.
Riddell DR, Zhou H, Atchison K, Warwick HK, Atkinson PJ, Jefferson J, Xu L, Aschmies S, Kirksey Y, Hu Y, Wagner E, Parratt A, Xu J, Li Z, Zaleska MM, Jacobsen JS, Pangalos MN, Reinhart PH.
Impact of apolipoprotein E (ApoE) polymorphism on brain ApoE levels.
J Neurosci. 2008 Nov 5;28(45):11445-53.
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